PROJECT SUMMARY/ABSTRACT The response to a severe burn is characterized by a persistent hypermetabolic and catabolic state that results in the loss of muscle tissue and bone, decreased growth rate, and increased oxidative stress and inflammation. Endogenous catecholamines and corticosteroids have been implicated as primary mediators of the hypermetabolic response to burn and trauma. Severe burns also critically decrease androgen production, which has been linked to impaired physical function, the loss of muscle mass, and an increased risk of bone fractures. The hypermetabolic response to burns is also characterized by a profound tachycardia and increased cardiac work that are detrimental to the heart; we have previously shown that these are attenuated by the daily use of the non-selective ?-1/?-2 adrenergic antagonist propranolol in severely burned children and adults, and have also shown a reduction in catecholamines with propranolol use. Propranolol is now part of our standard of care (SOC). Our preliminary data suggest that when our standard of care is administered to massively burned children in combination with the testosterone analog oxandrolone, there are improved responses in muscle and bone, as well as the cardiopulmonary and vascular systems, allowing whole-body accretion of lean body mass, improved muscle strength/function, and increased growth rate. Our central hypothesis is that regeneration and recovery in severely burned subjects will occur to a greater extent when androgen/corticosteroid production is modulated in conjunction with catecholamine decrease with the use of oxandrolone with the standard of care. A total of 300 subjects with burns ?30% TBSA (total burn surface area) will be randomized into either an Oxandrolone-treated group (`OX', 0.1 mg/kg twice per day of oxandrolone for one year) or the Standard of Care-treated group (`SOC' for one year): We will test our hypothesis in this phase II clinical trial by pursuing the following three specific aims: 1) To determine the effects of long-term OX administration on clinically relevant outcomes, as reflected by growth rate and growth arrest, length of hospital stay and psychosocial health; 2) To assess the effects of long-term OX on bone and muscle mass and their function, as reflected by strength and cardiopulmonary endurance; 3) To determine the effects of long-term OX on oxidative stress and the glucocorticoid response, as reflected by oxidant and antioxidant concentrations. Primary endpoints will include growth (in children only), length of hospital stay, psychosocial health, lean body mass, bone mineral content, bone and muscle strength, and cortisol and oxidant concentrations. Secondary outcomes will include endurance, resting energy expenditure, mortality, the incidence of infection, sepsis, and pneumonia, bone and muscle microstructure, and antioxidant concentrations. Clinical parameters will also be monitored for safety profile purposes. This innovative, randomized, prospective study will examine in an appropriate number of subjects the effects and potential molecular and biochemical mechanisms operating when modulation of androgen/corticosteroid pathways is combined with catecholamine control.